title: Is activation of the intra-S checkpoint in human fibroblasts an important factor in protection against UV-induced mutagenesis?
abstract: The ATR/CHK1-dependent intra-S checkpoint inhibits replicon initiation and replication fork progression in response to DNA damage caused by UV (UV) radiation. It has been proposed that this signaling cascade protects against UV-induced mutations by reducing the probability that damaged DNA will be replicated before it can be repaired. Normal human fibroblasts (NHF) were depleted of ATR or CHK1, or treated with the CHK1 kinase inhibitor TCS2312, and the UV-induced mutation frequency at the HPRT locus was measured. Despite clear evidence of S-phase checkpoint abrogation, neither ATR/CHK1 depletion nor CHK1 inhibition caused an increase in the UV-induced HPRT mutation frequency. These results question the premise that the UV-induced intra-S checkpoint plays a prominent role in protecting against UV-induced mutagenesis.
authors.affiliation: Curriculum in Toxicology; University of North Carolina-Chapel Hill; Chapel Hill, NC USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Sproul
authors.forename: Shangbang
authors.initials: S
authors.lastname: Rao
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Ibrahim
authors.forename: William K
authors.initials: WK
authors.lastname: Kaufmann
authors.forename: Marila
authors.initials: M
authors.lastname: Cordeiro-Stone
mesh_terms: D002460:Cell Line; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000528:radiation effects; D004261:DNA Replication / Q000528:radiation effects; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D056426:Genetic Loci; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D016296:Mutagenesis / Q000528:radiation effects*; D009154:Mutation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000502:physiology*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D007041:Hypoxanthine Phosphoribosyltransferase; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
keywords: ATR; CHK1; DNA damage response; cell cycle checkpoints; intra-S checkpoint; mutagenesis; ultraviolet radiation